Project Summary This proposal aims to extend our work investigating functional connectivity in the human cervical spinal cord (CSC) using resting state functional MRI (rsfMRI) to relate CSC function to 1) structural abnormalities and 2) clinical, neurological function in patients with multiple sclerosis (MS). We propose that functional connectivity as measured by spatially correlated blood oxygenation level dependent (BOLD) signals may provide an unprecedented biomarker for CSC function, recovery, and treatment in MS patients, for which there is currently no non-invasive imaging method. rsfMRI in the brain has been widely studied, yet similar studies in the CSC are lacking. Our group first reported detection and quantification of spatially correlated, low-frequency BOLD signal fluctuations in the CSC in a resting state in healthy volunteers and we show, herein, in patients with MS. Our scientific premise is that much of the neurological deterioration experienced by MS patients may arise from SC damage and in the resting state, alterations in neural synchrony responsible for maintenance of SC function will provide a novel, objective biomarker for studying the functional health of the CSC in MS patients. Our lab has also pioneered advanced, quantitative MRI (qMRI) for the CSC in MS, and we will, for the first time, relate changes in qMRI indices reflective of axonal and myelin health, as well as lesion burden, and tissue atrophy to alterations in resting-state CSC function. We propose to utilize technical developments for transitioning recent work to 3T, and also clinical validation of these approaches assessing the added value of CSC rsfMRI. We aim to 1) further develop robust, reliable methods to detect and quantify functional connectivity in the human CSC by optimizing acquisition and analysis for 3T deployment, 2) to relate rsfMRI abnormalities to structural, and qMRI (Diffusion Tensor Imaging and Quantitative Magnetization Transfer), and 3) to relate rsfMRI aberrations to neurological impairment, and evolution. rsfMRI will be related to spatial distribution of lesions, lesion burden, and qMRI-derived indices within and across CSC segments. Lastly, measurements of rsfMRI connectivity will be correlated with a battery of targeted neurological assessments that probe an MS patient?s neurological performance to establish the relevance of rsfMRI changes to MS impairment. We hypothesize that increased structural abnormalities will result in greater rsfMRI connectivity alterations, though neurological presentation may not be as easily related. Therefore, the significance of this proposal is that we will, for the first time, comprehensively assess CSC function and structure to understand the neurological-radiological discordance in patients with MS. If successful, we will establish that rsfMRI studies of the brain can be deployed to objectively evaluate functional circuitry and synchrony within the CSC and show that measures derived from CSC rsfMRI assessment are relevant for assessing clinically manifest function, or loss of function. The opportunity to assess functional connectivity in the resting state has further benefit in patients who have limited neurological function or present with spinal cord predominant disease.